The prevalence of diabetes mellitus (DM) has increased worldwide from 30 million in 1985 to 180 million currently, and is predicted to rise to 366 million by the year 2025. In developing countries such as China and India, the number of cases diagnosed with new onset DM is increasing at a stunning rate of 3,000 per day. And currently more than one in 400 children become insulin dependent due to Type 1 DM (T1DM), due to autoimmune-mediated destruction of pancreatic β cells. In 2003 in the USA there were 14.6 million individuals with the diagnosis of DM, 7% or 1.02 million of which were subjects with T1DM (Diabetes Atlas 2003). Despite treatment, often futile, with exercise, weight control, and oral agents, the vast majority of subjects with adult onset, Type 2 DM (T2DM), characterized by primary insulin resistance, will eventually become insulin dependent because of pancreatic β cell failure. This is associated with advanced manifestations of the diabetic state, such as retinopathy, neuropathy, nephropathy, and major cardiovascular and infectious complications, collectively resulting in ever increasing medical expenses, morbidity and mortality rates. In 2003 in Europe, a total of 48.4 million subjects were diagnosed with DM, and 7% of these or 3.5 million were subjects with T1DM. However, despite the life-sustaining actions of insulin injections in affected individuals by preventing diabetic ketoacidosis, exogenous insulin does not protect against secondary micro- and macro-vascular complications such as diabetic retinopathy (blindness), nephropathy (renal failure, dialysis dependency, need for kidney transplant), stroke, neuropathy, limb amputations, coronary artery disease with myocardial infarction, and congestive heart failure. The resulting shortened life span in affected subjects demonstrates that injected insulin is a suboptimal form of therapy. Currently, more optimal therapies to replace endogenous insulin in subjects with T1DM include glucose-responsive, closed-loop insulin pumps, whole pancreas transplants, often combined with a kidney transplant, or a pancreatic β cell or islet transplant. Both forms of transplant depend on the availability of suitable cadaveric donors. To date, approximately 1,200 subjects worldwide have been treated with islet transplants, while more than 75,000 received whole pancreas grafts.
The following challenges with these forms of therapy continue to limit the urgently needed, large scale establishment of these promising interventions: (i) the availability of sufficient cadaveric pancreas/islet donors is grossly inadequate, (ii) this scarcity is further aggravated because frequently two pancreas donors are needed in order to generate sufficient islet numbers for one recipient, (iii) since the ability to culture expand pancreatic islets in vitro is small, an appropriate β cell supply for subjects in need thereof is currently not available, (iv) islet survival in the portal vein, the site of islet transplantation, is limited due to immune and non-immune injuries, resulting in progressive return of partial or complete insulin dependency after one to five years, (v) the need for lifelong immunosuppressant drugs, to prevent rejection, in graft recipients is associated with major adverse effects such as serious infections, malignancies, and kidney failure.
Taken together, despite encouraging progress with islet and pancreas transplantation, these highly desirable forms of endogenous, physiologically regulated insulin replacement are hampered by the above challenges and have thus far provided successful therapy for only a very small fraction of subjects with T1DM. Islet or pancreas transplantation for improvement in the quality of life of subjects with insulin-dependent T2DM has not been considered because the primary defect in these is peripheral insulin resistance with secondary β cell failure. Thus, unless insulin resistance in these subjects can be eliminated, exhaustion of transplanted β cell and subsequent β cell failure will destroy the islet cell grafts, while exposing the subject to the high risks of immunosuppressive drugs.
Very promising pre-clinical in vitro and animal studies and a few early phase clinical trials have demonstrated that pluripotent Mesenchymal Stem Cells or Marrow Stromal Cells (MSC) possess immunomodulating capabilities by inhibiting the T-cell or rejection response. MSC can be readily harvested from the bone marrow of a donor (allogeneic source) or a subject (autologous source), expanded in culture, differentiated into cells of mesodermal and non-mesodermal phenotype, cryopreserved, and administered for organ repair (e.g., kidney, heart, spinal cord, brain, or bone), as adjuvant to a bone marrow transplant with hematopoietic stem cells (HSC), for the treatment of grade IV Graft versus Host Disease, osteogenesis imperfecta, Hurler's syndrome, and other indications. Long term studies have shown that MSC do not undergo malignant transformation, a concern that potentially affects embryonic stem cell therapies. And, the utilization of these cells is not afflicted by ethical concerns.
In conclusion, a need exists for the development and clinical testing and introduction of fundamentally novel therapies for subjects with T1DM. Cell based new technologies that successfully address the challenges and obstacles that are currently encountered with islet cell transplantation (see above) are expected to dramatically increase the number of diabetic subjects that can receive long lasting replacement of endogenous insulin.